Circulating Protein and Metabolite Correlates of Histologically Confirmed Diabetic Kidney Disease.

Rationale & Objective: Diabetic kidney disease (DKD) is one of the leading causes of end-stage kidney disease globally. We aim to identify proteomic and metabolomic correlates of histologically confirmed DKD that may improve our understanding of its pathophysiology.

Study Design: A cross-sectional study.

Plasma proteomics of acute tubular injury.

The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development.

Quantification of Multi-Compartment Flow with Spectral Diffusion MRI.

Purpose: Estimation of multi-compartment intravoxel 'flow' in in ml/100g/min with multi-b-value diffusion weighted imaging and a multi-Gaussian model in the kidneys.

Theory And Methods: A multi-Gaussian model of intravoxel flow using water transport time to quantify (ml/100g/min) is presented and simulated. Multi-compartment anisotropic DWI signal is simulated with Rician noise and SNR=50 and analyzed with a rigid bi-exponential, a rigid tri-exponential and diffusion spectrum imaging model of intravoxel incoherent motion (spectral diffusion) to study extraction of multi-compartment flow.

Focal Segmental Glomerulosclerosis.

Focal segmental glomerular sclerosis (FSGS) is a histological lesion characterized by sclerosis in sections (segmental) of some glomeruli (focal) in association with podocyte injury. Historically, FSGS has often been characterized as a disease, but it is a heterogeneous entity based on etiology, clinical course, and therapeutic approach. A unifying feature is podocyte injury and loss, which can be primary or the result of secondary maladaptive responses to glomerular stressors.

Plasma Proteins Associated with Chronic Histopathologic Lesions on Kidney Biopsy.

Key Points: Proteomic profiling identified 35 blood proteins associated with chronic histopathologic lesions in the kidney. Testican-2 was expressed in the glomerulus, released by the kidney into circulation, and inversely associated with glomerulosclerosis severity. NELL1 was expressed in tubular epithelial cells, released by the kidney into circulation, and inversely associated with interstitial fibrosis and tubular atrophy severity.

Defining the Nature and Clinicopathologic Significance of Mallory-Denk-like Inclusions in Ovarian Fibromas: A Potential Degenerative Phenomenon Associated With Torsion.

Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree.

Defining the molecular correlate of arteriolar hyalinosis in kidney disease progression by integration of single cell transcriptomic analysis and pathology scoring.

Arteriolar hyalinosis in kidneys is an independent predictor of cardiovascular disease, the main cause of mortality in chronic kidney disease (CKD). The underlying molecular mechanisms of protein accumulation in the subendothelial space are not well understood. Using single cell transcriptomic data and whole slide images from kidney biopsies of patients with CKD and acute kidney injury in the Kidney Precision Medicine Project, the molecular signals associated with arteriolar hyalinosis were evaluated.

The use of plasma biomarker-derived clusters for clinicopathologic phenotyping: results from the Boston Kidney Biopsy Cohort.

Background: Protein biomarkers may provide insight into kidney disease pathology but their use for the identification of phenotypically distinct kidney diseases has not been evaluated.

Methods: We used unsupervised hierarchical clustering on 225 plasma biomarkers in 541 individuals enrolled into the Boston Kidney Biopsy Cohort, a prospective cohort study of individuals undergoing kidney biopsy with adjudicated histopathology. Using principal component analysis, we studied biomarker levels by cluster and examined differences in clinicopathologic diagnoses and histopathologic lesions across clusters.

Circulating Plasma Biomarkers in Biopsy-Confirmed Kidney Disease.

Background And Objectives: Biomarkers for noninvasive assessment of histopathology and prognosis are needed in patients with kidney disease.

Design, Setting, Participants, & Measurements: Using a proteomics assay, we measured a multimarker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semiquantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as ≥40% decline in eGFR or initiation of KRT) and death.

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

Rationale & Objective: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) is associated with lower tubular secretory clearance in persons undergoing kidney biopsy.

Study Design: Cross-sectional.

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease.

People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease.

Plasma Kidney Injury Molecule 1 in CKD: Findings From the Boston Kidney Biopsy Cohort and CRIC Studies.

Rationale & Objective: Plasma kidney injury molecule 1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown.

Study Design: Prospective, observational cohort study.

Setting & Participants: 524 individuals enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by 2 kidney pathologists and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study.

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed.

IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation.

Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines.

Serotonin Transporter Ala276 Mouse: Novel Model to Assess the Neurochemical and Behavioral Impact of Thr276 Phosphorylation In Vivo.

The serotonin (5-HT) transporter (SERT) is a key regulator of 5-HT signaling and is a major target for antidepressants and psychostimulants. Human SERT coding variants have been identified in subjects with obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) that impact transporter phosphorylation, cell surface trafficking and/or conformational dynamics. Prior to an initial description of a novel mouse line expressing the non-phosphorylatable SERT substitution Thr276Ala, we review efforts made to elucidate the structure and conformational dynamics of SERT with a focus on research implicating phosphorylation at Thr276 as a determinant of SERT conformational dynamics.

Aberrantly glycosylated IgG elicits pathogenic signaling in podocytes and signifies lupus nephritis.

Lupus nephritis (LN) is a serious complication occurring in 50% of patients with systemic lupus erythematosus (SLE) for which there is a lack of biomarkers, a lack of specific medications, and a lack of a clear understanding of its pathogenesis. The expression of calcium/calmodulin kinase IV (CaMK4) is increased in podocytes of patients with LN and lupus-prone mice, and its podocyte-targeted inhibition averts the development of nephritis in mice. Nephrin is a key podocyte molecule essential for the maintenance of the glomerular slit diaphragm.

The Associations of Plasma Biomarkers of Inflammation With Histopathologic Lesions, Kidney Disease Progression, and Mortality-The Boston Kidney Biopsy Cohort Study.

Background: Soluble tumor necrosis factor receptor (sTNFR)-1, sTNFR-2, YKL-40, monocyte chemoattractant protein (MCP)-1, and soluble urokinase plasminogen activator receptor (suPAR) have emerged as promising biomarkers of inflammation but have not been evaluated across diverse types of kidney diseases.

Methods: We measured these plasma biomarkers in 523 individuals enrolled into a prospective, observational cohort study of patients undergoing clinically indicated native kidney biopsy at 3 tertiary care hospitals. Two kidney pathologists adjudicated biopsy specimens for semiquantitative scores of histopathology.

More Specialties, Fewer Problems: Using Collaborative Competency Between Infectious Diseases, Podiatry, and Pathology to Improve the Care of Patients with Diabetic Foot Osteomyelitis.

Background: Diabetic foot osteomyelitis is a common infection where treatment involves multiple services, including infectious diseases, podiatry, and pathology. Despite its ubiquity in the hospital, consensus on much of its management is lacking.

Methods: Representatives from infectious diseases, podiatry, and pathology interested in quality improvement developed multidisciplinary institutional recommendations culminating in an educational intervention describing optimal diagnostic and therapeutic approaches to diabetic foot osteomyelitis (DFO).

Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 in Papillary Thyroid Carcinoma.

BRAF acts as an ATP-dependent cytosolic kinase. BRAF inhibitors are widely available, but resistance to them is widely reported in the clinic. Lipid metabolism (fatty acids) is fundamental for energy and to control cell stress.

Mitochondrial transplantation by intra-arterial injection for acute kidney injury.

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters.